title: Glioma-derived macrophage migration inhibitory factor (MIF) promotes mast cell recruitment in a STAT5-dependent manner.
abstract: Recently, glioma research has increased its focus on the diverse types of cells present in brain tumors. We observed previously that gliomas are associated with a profound accumulation of mast cells (MCs) and here we investigate the underlying mechanism. Gliomas express a plethora of chemoattractants. First, we demonstrated pronounced migration of human MCs toward conditioned medium from cultures of glioma cell lines. Subsequent cytokine array analyses of media from cells, cultured in either serum-containing or -free conditions, revealed a number of candidates which were secreted in high amounts in both cell lines. Among these, we then focused on macrophage migration inhibitory factor (MIF), which has been reported to be pro-inflammatory and -tumorigenic. Infiltration of MCs was attenuated by antibodies that neutralized MIF. Moreover, a positive correlation between the number of MCs and the level of MIF in a large cohort of human glioma tissue samples was observed. Further, both glioma-conditioned media and purified MIF promoted differential phosphorylation of a number of signaling molecules, including signal transducer and activator of transcription 5 (STAT5), in MCs. Inhibition of pSTAT5 signaling significantly attenuated the migration of MCs toward glioma cell-conditioned medium shown to contain MIF. In addition, analysis of tissue microarrays (TMAs) of high-grade gliomas revealed a direct correlation between the level of pSTAT5 in MCs and the level of MIF in the medium. In conclusion, these findings indicate the important influence of signaling cascades involving MIF and STAT5 on the recruitment of MCs to gliomas.
authors.affiliation: Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden. Electronic address: jelena.polajeva@igp.uu.se.
authors.forename: Jelena
authors.initials: J
authors.lastname: Põlajeva
authors.affiliation: Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden. Electronic address: tobias.bergstrom@igp.uu.se.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bergström
authors.affiliation: Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden. Electronic address: per-henrik.edqvist@igp.uu.se.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Edqvist
authors.affiliation: Swedish University of Agricultural Sciences, Department of Anatomy, Physiology and Biochemistry, BMC, Box 575, SE-751 23 Uppsala, Sweden. Electronic address: lundequist@gmail.com.
authors.forename: Anders
authors.initials: A
authors.lastname: Lundequist
authors.affiliation: Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Sjösten
authors.affiliation: Karolinska Institutet, Department of Medicine, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden. Electronic address: gunnar.p.nilsson@ki.se.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Nilsson
authors.affiliation: Uppsala University Hospital, Department of Neuroscience, Neurology, SE-751 85 Uppsala, Sweden. Electronic address: anja.smits@neuro.uu.se.
authors.forename: Anja
authors.initials: A
authors.lastname: Smits
authors.affiliation: Uppsala University Hospital, Department of Neuroscience, Neurology, SE-751 85 Uppsala, Sweden. Electronic address: michael.bergqvist@onkologi.uu.se.
authors.forename: Michael
authors.initials: M
authors.lastname: Bergqvist
authors.affiliation: Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden. Electronic address: fredrik.ponten@igp.uu.se.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.affiliation: Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden. Electronic address: bengt.westermark@igp.uu.se.
authors.forename: Bengt
authors.initials: B
authors.lastname: Westermark
authors.affiliation: Swedish University of Agricultural Sciences, Department of Anatomy, Physiology and Biochemistry, BMC, Box 575, SE-751 23 Uppsala, Sweden. Electronic address: gunnar.pejler@slu.se.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Pejler
authors.affiliation: Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden. Electronic address: karin.nilsson@igp.uu.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Forsberg Nilsson
authors.affiliation: Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden. Electronic address: elena.chugunova@igp.uu.se.
authors.forename: Elena
authors.initials: E
authors.lastname: Tchougounova
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology*; D050799:STAT5 Transcription Factor / Q000378:metabolism*
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D050799:STAT5 Transcription Factor
keywords: BBB; CBMC; CF; CI; GBM; Glioma; IHC; MC; MIF; Mast cell; STAT; TMA; blood–brain barrier; cord blood mast cell; cytoplasmic fraction; cytoplasmic intensity; glioblastoma multiforme; immunohistochemistry; mast cell; microphage migration inhibitory factor; pSTAT5; signal transducer and activator of transcription; tissue microarray